LITERATURE REVIEW

Short-Acting Tryptamines as Alternative Treatments for Substance-Use Disorders

1.2 WHY ARE SUBSTANCE-USE DISORDERS SO HARD TO TREAT?

Figure 1. This figure shows the complex three stages of addiction; withdrawal/ negative affect, preoccupation/anticipation “craving,” and binge/intoxication, and all the circuitry between structures (Koob & Volkow, 2010).

1.3 HOW CAN WE TRANSLATE FINDINGS INTO CLINICAL INTERVENTIONS?

2 METHODS

2.1 METHODS FOR LITERATURE REVIEW

3.4 NOTABLE CONSIDERATIONS

4 DISCUSSION

4.1 PSYCHOLOGICAL IMPLICATIONS

4.2 NEUROSCIENTIFIC IMPLICATIONS

Figure 2. This visualizes top-down information processing (top) and bottom-up processing (bottom) and their regional implications in the REBUS & the anarchic brain model (Carhart-Harris & Friston, 2019).

5 REFERENCES

ABSTRACT

This article is a literature review of short-acting tryptamines, such as 5-MeO-DMT and N,N-DMT, as potential options for treating substance-use disorders. As clinical trials for ketamine, MDMA, and psilocybin-assisted therapies for numerous disorders continue to unfold, there are many commonalities bubbling up to the surface, refining methods for future use. There is a disappointing scarcity in information regarding short-acting tryptamines and their consideration as alternative treatments for various conditions, especially substance-use disorders.

As interest in alternative treatments for psychiatric disorders continues to grow, it should be noted that this article doesn’t aim to replace traditional treatments but rather expand the options for patients suffering from various treatment-resistant disorders, unresponsive to traditional forms of treatment. Short-acting tryptamines are potent psychoactive substances capable of causing brief and intense psychedelic effects when consumed, creating unique circumstances for facilitating sessions. Despite their common affinity for serotonergic pathways like other psychoactive tryptamines, their duration and intensity create a curious dynamic when attempting to translate methods from other protocols. With the rise of studies exploring the implications of serotonergic networks in facilitating periods of cognitive behavioral plasticity, scientists are getting closer to unlocking previously untapped potential lying beyond the peripheries of the scope of traditional treatment.

This article assesses the safety, benefits, concerns, and important results of previous research/ experiences about short-acting tryptamines in regard to treating underlying psychiatric conditions, specifically substance-use disorders. Additionally, this article explains the implications of short-acting tryptamines in psychology and neuroscience for treating substance use disorders.

1 INTRODUCTION

1.1 WHAT ARE SHORT-ACTING TRYPTAMINES?

N, N-dimethyltryptamine, and 5-MeO-dimethyltryptamine are psychedelic substances falling under the chemical class of tryptamines. This class includes endogenous chemicals like melatonin, serotonin and other molecules such as psilocybin and baeocystin, the active constituents of psychedelic mushrooms. Despite their similarities with other psychedelic compounds, they differ in many ways.

Depending on the substance concentration, dosage, and route of administration, the duration of short-acting tryptamines is variable. It should be dutifully noted that 5-MeO-DMT is overall more potent than N-N-DMT and elicits a vastly different subjective experience. This distinguishment must be made, as results between the two may vary. Both have relatively short durations ranging from 10-30 minutes and are administrable by insufflation, vaporization, injection, and when coupled with MAOIs, it can result in a prolonged duration of 4-6 hours, a concoction referred to as ayahuasca (Riba, et al., 2003).

The indigenous use of DMT in the form of ayahuasca has been prevalent throughout medicinal ceremonies for centuries and is starting to gain surprising empirical support as more neuro-regenerative and protective properties of short-acting tryptamines are discovered. It is important to consider its historical use as we examine its potential in the clinical space.

1.2 WHY ARE SUBSTANCE-USE DISORDERS SO HARD TO TREAT?

As of 2022, over 20 million Americans over the age of 12 are affected by substance-use disorders (NCDAS, 2022). Addiction comes in a variety of forms and is different with every substance and takes different forms. Some of the most common drugs associated with addiction, such as methamphetamine and heroin, are some of the hardest to treat, and traditional treatment has been spread thin to stop this trend, but it may not be enough.

According to the National Institute for Drug Abuse, 87% of individuals relapse after treatment, which are abhorrent statistics, which are unacceptable, and indicative of a reevaluation of the whole system for treatment. DMT may have the potential to disrupt addiction enough to give patients the ability to recover, but the mechanisms as to how it works are still unclear. Their short-acting duration and nonaddictive properties show low potential for dependence and have sparked interest in research throughout academia (Reckweg et al., 2021).

Substance use disorders are different than normal mental health issues and have a reputation for being resistant to treatment. Considering the complexity of substance-use disorders, traditional treatments struggle to address the multi-faceted issue. Short-acting tryptamines can induce “spiritual breakthroughs,” which promotes deep psychological introspection; this perspective may be a great place to start for recovery (Lafrance, et al., 2021).

Figure 1. This figure shows the complex three stages of addiction; withdrawal/ negative affect, preoccupation/anticipation “craving,” and binge/intoxication, and all the circuitry between structures (Koob & Volkow, 2010).

1.3 HOW CAN WE TRANSLATE FINDINGS INTO CLINICAL INTERVENTIONS?

As new protocols in psychedelic assisted therapies are being refined by trials, such as MDMA for PTSD and ketamine for depression, it is important to lay a foundation to explore the beneficial potential of other psychedelic compounds and how they could be used for other clinical purposes.

Preparation, facilitation, and integration are three stages used throughout psychedelic therapies. Every step is important but integration is crucial to ensuring long-term benefits, as relapse has been a pervasive obstacle in the path of recovery.

The legality of psychedelics has hindered research, but private research companies have taken initiative, commencing early stages of clinical research on these substances, and show potential for expediting their clinical implementation.

2 METHODS

2.1 METHODS FOR LITERATURE REVIEW

A thorough literature search was carried out using the databases: National Center for Biotechnology Information, PsycINFO®, SCOPUS™, BIOSIS, ResearchGate, and Elsevier on March 5th 2022 with preference for studies published in the last decade. Search terms included: 5-MeO-DMT; N,N-DMT; substance-use disorders; alternative treatments for addiction; chemical dependency; psychedelics; psychoactive; cognition; dose-finding; fMRI; EEG; anxiety; depression; spirituality; emotion regulation; epidemiology; tryptamines; serotonin; psychedelic-assisted therapy; hallucinogens; and entheogen. Relevant clinical and preclinical studies conducted in English were included. Literature was reconsidered if the publications were non-empirical research studies, studies with an n less than 10; editorials, opinion articles, protocols, abstracts, proceedings, conceptual analyses, case studies, patient resources, or reviews. The search produced over 200 studies of which only 40 were considered and further refined to 13. By investigating these remaining studies with this paper seeks to make an informed argument as to why these substances should be studied further for addiction and more.

2.2 LIMITATIONS

Some of the studies were overwhelmingly white heterosexual males around the age of 35 the data may be skewed or limited. There is a big range in demographics involved in the studies as some are extensive and thorough and others briefly mention their demographics, focusing more on the specific data from fMRI or various extensive questionnaires. There was a variety in number of subjects and inclusions, with populations localizing from the firstly the North American region, right after European regions.

3 RESULTS

3.1 SAFETY

There are still many nascent studies who have yet to upload their results and therefore results are still in progress. Numerous studies evaluating the safety of these compounds, multiple results came to similar conclusions (Davis, et al., ). In a phase 1 clinical trial studying the dose dependent outcomes of 5-MeO-DMT, no adverse events led to withdrawal of trial, and no serious adverse events occurred (Reckweg et al., 2021).

3.2 BENEFITS

One study conducted in 2019, showed that after a single administration, rapid and persistent improvements in satisfaction with life, mindfulness, and psychopathological symptoms, are associated with the higher dosages (Uthaug et al., 2018; Strassman & Qualls, 1992). After the various dose experiments on subjects it could be confidently said that higher doses elicited higher ratings in various inventories, most interestingly the mythical experience questionnaire. Some studies have even shown benefits from continuous micro dosing (Cameron, 2019). After administering short-acting tryptamines to healthy subjects with varying doses and conducting multiple surveys, the safety of these compounds could be better understood. These conclusions may point to many indications. Firstly, that these mystical states of consciousness may induce a deep state of reflection and this self-reflection may be one of the main contributors to this treatment’s success.

This leads to the next supplemental aspect which is the importance of spirituality and emotional regulation. In supplementary studies the connection between spirituality and psychedelic use was found and as more data revealed, higher scores of spirituality corresponded with their emotional regulation levels. By giving a number of questionnaires including World Health Organization Spirituality, Religiousness, and Personal Beliefs (WHOQOL-SRPB), difficulties in emotion regulation (DERS), Center for Epidemiologic Studies Depression Scale Revised (CESD-R), and Eating Disorders Examination Questionnaire (EDE-Q), we were able to deduce that the cultivation of spirituality, which may or may not be propelled by psychedelic use, has a positive effect of emotional regulation. Some of the limitations of the research were that the demographic section was sparce and gave a brief background on the demographics which could be seen as rather inconclusive. In summation, psychedelics can illicit states of spirituality which could be translated to a higher likelihood for better emotional regulation, which in turn had an impact on subjects abilities to handle stress related conditions specifically eating disorders and depression (Lafrance, et al., 2021).

3.3 CONCERNS

Some of the primary concerns stem from the physical effects of the experience; including cardiovascular stress, and the psychological repercussions of being unprepared and exposed to short-acting tryptamines, especially due to its psychotomimetic characteristics. In one of the first clinical studies ever conducted N,N-DMT was dose-dependently found to elevate blood pressure, heart rate, pupil diameter, and rectal temperature, in addition to elevating blood concentrations of beta-endorphin, corticotropin, cortisol, and prolactin (Strassman & Qualls, 1992). These rises in levels are indicative of acute stress and could lead to potential traumas. Further research is needed to evaluate its effects on the genome and other time-dependent factors.

3.4 NOTABLE CONSIDERATIONS

To understand how short acting tryptamines could potentially be used for treating SUDs, we took a close look at representative data to see how and why short acting tryptamines and similar substances could be efficacious for treating SUDs, and potentially translated to other disorders after expanding our understanding of their novel mechanisms.

Many of the studies’ results were conducive to their use in the therapeutic setting, and even included some positive reports outside the clinical setting. As for their indication in the face of chemical dependency, there is still more research that needs to be done. The biological findings seem to support the psychological outcomes but there is still much research to be done before these substances can be clinically implemented.

4 DISCUSSION

4.1 PSYCHOLOGICAL IMPLICATIONS

After evaluating the safety of short-acting tryptamines, it could reasonably be concluded that in the proper setting with the proper resources these experiences can be safe with the exception of some outliers who may have encountered adverse effects. Whether or not these experiences were safe was concluded through surveys of subjects from the internet, inventorying aspects and notable improvements after the experiences. Some parameters measured were how often they use short-acting tryptamines, different issues after their experiences, such as craving the experience again, medical, psychiatric, and or legal problems. The surveys revealed that there were little to no adverse reactions concerning psychiatric, medical, and legal problems and only a small portion of the population had cravings to partake in the experience again (Hallack, et al., 2017). It is very interesting to find that an overwhelming majority of participants experienced improvements in PTSD, depression, anxiety, alcoholism, and drug-use disorder. These findings are conclusive that potential for abusing short-acting tryptamines is low, and predominantly used for spiritual exploration, and they may have psychotherapeutic use (Cozzi, et al., 2009).

As recent research suggests, DMT models the near-death experience, which may for many reasons cause an individual to reconsider much of their actions (Timmerman, et al., 2018).

4.2 NEUROSCIENTIFIC IMPLICATIONS

In a study that explored the biological effects of short acting tryptamines, we can interpret how the excitatory effects can have an increasing neurogenesis and/or spinogenesis. Through both in vitro and in vivo experiments measuring results of brain activity in primary cortical cultures before and after administration this study was able to make interesting finding supporting the claims. Naturally, the limitations are that there is big gap between rat and human brain translations but this gives hope to researchers in the field. It can be concluded that short-acting tryptamines may have neurogenesis and/or spinogenesis properties in humans, and as depression and anxiety can be seen as atrophy in the prefrontal cortex, these substances could increase change in neuronal structures like neuron number and function (Ly, et al., 2018). In summation, short-acting tryptamines could potentially be used for their plasticity-promoting properties and could be effective fast-acting treatments for depression and related disorders.

Some of the leading theories as to psychedelics' benefits include relaxed beliefs under psychedelics (REBUS) and the anarchic brain. Through these concepts presented, psychedelics work to relax the precision of high-level priors or beliefs and flip top-down processing (prior beliefs are projected onto outside stimulus) into bottom-up processing (outside stimulus is seen as novel or never before seen) by facilitation of the limbic system. Some of the leading theories as to psychedelics' benefits include relaxed beliefs under psychedelics (REBUS) and the anarchic brain. Through these concepts presented, psychedelics work to relax the precision of high-level priors or beliefs and flip top-down processing (prior beliefs are projected onto outside stimulus) into bottom-up processing (outside stimulus is seen as novel or never before seen) by facilitation of the limbic system.

Figure 2. This visualizes top-down information processing (top) and bottom-up processing (bottom) and their regional implications in the REBUS & the anarchic brain model (Carhart-Harris & Friston, 2019).

The neurocircuitry of addiction is truly sinister and has various stages incorporating various parts of the brain. By increasing entropy and priming work against conditioned cues engrained into the hippocampus, which compromise the frontal cortex or the decision-making center, psychedelics could potentially re-empower this autonomy through prefrontal cortex activation coupled with the flipped information processing, cultivating periods of reflection/ reevaluation of priors to potentially enduring revisions (Koob & Volkow, 2010; Carhart-Harris & Friston, 2019; Herzog, et al., 2020).

5 REFERENCES

1. Anon (2022) Substance abuse and addiction statistics [2022]. NCDAS Available at: https://drugabusestatistics.org/ [Accessed May 5, 2022].

2. Cameron LP, Benson CJ, DeFelice BC, Fiehn O, Olson DE (2019) Chronic, intermittent microdoses of the psychedelic n,n-dimethyltryptamine (DMT) produce positive effects on mood and anxiety in rodents. ACS chemical neuroscience Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639775/ [Accessed May 6, 2022].

3. Carhart-Harris RL, Friston KJ (2019) Rebus and the anarchic brain: Toward a unified model of the brain action of psychedelics. Pharmacological reviews Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588209/ [Accessed May 6, 2022].

4. Cozzi NV, Gopalakrishnan A, Anderson LL, Feih JT, Shulgin AT, Daley PF, Ruoho AE (2009) Dimethyltryptamine and other hallucinogenic tryptamines exhibit substrate behavior at the serotonin uptake transporter and the vesicle monoamine transporter - journal of neural transmission. SpringerLink Available at: https://link.springer.com/article/10.1007/s00702-009-0308-8 [Accessed March 6, 2022].

5. Davis AK, Barsuglia JP, Lancelotta R, Grant RM, Renn E (2018) The epidemiology of 5-methoxy- N, N-dimethyltryptamine (5-MEO-DMT) use: Benefits, consequences, patterns of

use, subjective effects, and reasons for consumption. Journal of psychopharmacology (Oxford, England) Available at: https://pubmed.ncbi.nlm.nih.gov/29708042/ [Accessed March 6, 2022].

6. Lafrance A, Strahan E, Bird BM, St. Pierre M, Walsh Z (2021) Classic Psychedelic Use and Mechanisms of Mental Health: Exploring the Mediating Roles of Spirituality and Emotion Processing on Symptoms of Anxiety, Depressed Mood, and Disordered Eating in a Community Sample. SAGE Journals Available at: https://journals.sagepub.com/doi/full/10.1177/00221678211048049 [Accessed March 6, 2022].

7. Lawn W, Hallak JE, Crippa JA, Dos Santos R, Porffy L, Barratt MJ, Ferris JA, Winstock AR, Morgan CJA (2017) Well-being, problematic alcohol consumption and acute subjective drug effects in past-year ayahuasca users: A large, international, self-selecting online survey. Nature News Available at: https://www.nature.com/articles/s41598-017-14700-6 [Accessed March 6, 2022].

8. Ly C, Greb AC, Cameron LP, Wong JM, Barragan EV, Wilson PC, Burbach KF, Zarandi SS, Sood A, Paddy MR, Duim WC, Dennis MY, McAllister AK, Ori-McKenney KM, Gray JA, Olson DE (2018) Psychedelics promote structural and functional neural plasticity. Cell Reports Available at: https://www.sciencedirect.com/science/article/pii/S2211124718307551?pes=vor#sec4 [Accessed March 7, 2022].

9. Reckweg J, Mason NL, van Leeuwen C, Toennes SW, Terwey TH, Ramaekers JG (2021) A phase 1, dose-ranging study to assess safety and psychoactive effects of a vaporized 5-methoxy-N, N-dimethyltryptamine formulation (GH001) in Healthy Volunteers. Frontiers Available at: https://www.frontiersin.org/articles/10.3389/fphar.2021.760671/full [Accessed March 6, 2022].

10. Riba J, Valle M, Urbano G, Yritia M, Morte A, Barbanoj MJ (2003) Human pharmacology of ayahuasca: Subjective and cardiovascular effects, monoamine metabolite excretion, and pharmacokinetics. Journal of Pharmacology and Experimental Therapeutics Available at: https://jpet.aspetjournals.org/content/306/1/73.long [Accessed March 7, 2022].

11. Strassman RJ, Qualls CR (1994) Dose-response study of N,N-dimethyltryptamine in humans. I. Neuroendocrine, autonomic, and cardiovascular effects. Archives of general psychiatry Available at: https://pubmed.ncbi.nlm.nih.gov/8297216/ [Accessed May 5, 2022].

12. Timmermann C, Roseman L, Williams L, Erritzoe D, Martial C, Cassol H, Laureys S, Nutt D, Carhart-Harris R (2018) DMT models the near-death experience. Frontiers Available at: https://www.frontiersin.org/articles/10.3389/fpsyg.2018.01424/full [Accessed March 6, 2022].

13. Uthaug MV, R. Lancelotta, K. van Oorsouw, K. P. C. Kuypers, N. Mason, J. Rak, A. Šuláková, R. Jurok, M. Maryška, M. Kuchař, T. Páleníček, J. Riba, J. G. Ramaekers (2019) A single inhalation of vapor from dried toad secretion containing5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) in a naturalistic setting is related to sustained enhancement of satisfaction with life, mindfulness-related capacities, and a decrement of psychopathological symptoms. research gate Available at: https://www.researchgate.net/publication/332404598_A_single_inhalation_of_vapor_from_dried_toad_secretion_containing_5-methoxy-NN-dimethyltryptamine_5-MeO-DMT_in_a_naturalistic_setting_is_related_to_sustained_enhancement_of_satisfaction_with_life_mind/fulltext/5cb28a444585156cd7964b0c/A-single-inhalation-of-vapor-from-dried-toad-secretion-containing-5-methoxy-N-N-dimethyltryptamine-5-MeO-DMT-in-a-naturalistic-setting-is-related-to-sustained-enhancement-of-satisfaction-with-life-mi.pdf [Accessed March 6, 2022].

14. Herzog R, Mediano PAM, Rosas FE, Carhart-Harris R, Perl YS, Tagliazucchi E, Cofre R (2020) A mechanistic model of the neural entropy increase elicited by psychedelic drugs. Nature News Available at: https://www.nature.com/articles/s41598-020-74060-6 [Accessed March 6, 2022].

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